Genetic linkage mapping of Anopheles gambiae pedigrees in Africa identified a small Plasmodium- Resistance Island (PRI) of the genome that controls most of the natural genetic variation for mosquito resistance to Plasmodium falciparum infection. The PRI occupies -15 megabase pairs on chromosome 2L. Pedigree analysis was an efficient method for initial discovery of resistance loci, but pedigrees do not contain enough recombinational information to genetically identify the actual causative gene(s) among the 1,000 genes within the resistance island. In contrast, the method of genetic association takes advantage of historic recombination in the natural population to dissect a locus to the single-gene level. Here we propose a genetic association study to identify the underlying specific genes that control resistance and susceptibility of A. gambiae to P. falciparum in nature, with the following Aims. Aim 1, we will construct an association panel by rearing wild-caught A. gambiae larvae in the insectary, and challenging them with P. falciparum from the blood of naturally-infected volunteers. Aim 2, we will carry out an indirect association study to narrow the target interval controlling resistance, using as neutral markers microsatellites and single-nucleotide polymorphisms. Aim 3, we will carry out a direct association study by resequencing part or all of the narrowed candidate region ascertained in Aim 2, to detect the genes that underlie control of mosquito resistance and susceptibility to malaria parasites in nature. The resulting information will allow specific discrimination of the genetically susceptible fraction of the mosquito population. The previous pedigree linkage study indicated that efficient mechanisms of genetic resistance are widespread in the vector population, and suggested that actual malaria transmission is carried out by a discrete subset of genetically susceptible mosquitoes. We propose that it may be possible to develop a novel form of malaria control based on specifically targeting the susceptibles to reduce their frequency in the vector population. Relevance: It may be possible to develop new strategies for malaria control focusing on the mosquito vector. Knowledge of the genetic mechanisms that affect transmission of malaria by vector mosquitoes would aid in the development of such vector-based control strategies.